Stearoyl CoA desaturases (SCD's) are Δ9 fatty acid desaturases. The mammalian enzymes are localized to the endoplasmic reticulum and require molecular O2 and NADH to desaturate saturated fatty acids at the Δ9 position and generate monounsaturated fatty acids and water in the process. The primary substrates for these enzymes are the acyl-CoA derivatives of stearic (C18) and palmitic acids (C16) with the major reaction being the conversion of stearic acid to oleate (C18:1). Depending on the species, 2-4 isoforms of SCD exist. In rodents these isoforms are highly homologous and differ primarily in tissue distribution. In humans there are 2 known isoforms (SCD1 and SCD5) and these isoforms function similarly, but SCD5 has reduced sequence homology to other SCD isoforms. Based on tissue distribution SCD5 appears to functionally analogous to rodent SCD2.
The best characterized SCD isozyme is SCD1 which is primarily found in liver, adipose and skeletal muscle. Deletion, mutation or inhibition of SCD1 in mice and rats results in decreased hepatic triglyceride secretion, decreased hepatic triglycerides and steatosis, resistance to weight gain and improvements in insulin sensitivity and glucose uptake (reviewed in Ntarnbi et al. (2004) Prog Lipid Res 43, 91-104; (2005), Prostaglandins Leukot. Essent. Fatty Acids 73, 35-41; and (2005) Obes. Rev. 6, 169-174. These studies combined with studies in humans showing correlations between surrogates for SCD activity and obesity strongly implicate SCD inhibition as a means to treat obesity, hypertryglyceridemia and associated diseases and co-morbidities. Studies done using antisense oligonucleotide inhibitors have also confirmed the results of the SCD1 knockout and asebia mouse studies, and clearly shown that hepatic SCD inhibition may reduce elevated hepatic glucose output; see Jiang et al. (2005) J. Clin. Invest. 115:1030-1038G. and Gutierrez-Juarez et al. (2006) J. Clin. Invest. 116:1686-1695.
The present invention presents compounds that are useful in inhibiting SCD activity and thus regulating tissue and plasma lipid levels and fatty acid composition. These compounds are useful in the treatment of SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, including, but not limited to diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome, fatty liver diseases, and the like.